Journal of Immunotoxicology最新文献

{"title":"Epicutaneous challenge with protease allergen requires its protease activity to recall T_H2 and T_H17/T_H22 responses in mice pre-sensitized via distant skin.","authors":"Akira Ogasawara,&nbsp;Takuo Yuki,&nbsp;Toshiro Takai,&nbsp;Kyosuke Yokozeki,&nbsp;Asuka Katagiri,&nbsp;Yutaka Takahashi,&nbsp;Hiroo Yokozeki,&nbsp;David Basketter,&nbsp;Hitoshi Sakaguchi","doi":"10.1080/1547691X.2021.1968548","DOIUrl":"https://doi.org/10.1080/1547691X.2021.1968548","url":null,"abstract":"<p><p>Epicutaneous exposure to allergenic proteins is an important sensitization route for skin diseases like protein contact dermatitis, immunologic contact urticaria, and atopic dermatitis. Environmental allergen sources such as house dust mites contain proteases, which are frequent allergens themselves. Here, the dependency of T-helper (T_H) cell recall responses on allergen protease activity in the elicitation phase in mice pre-sensitized via distant skin was investigated. Repeated epicutaneous administration of a model protease allergen, i.e. papain, to the back skin of hairless mice induced skin inflammation, serum papain-specific IgE and T_H2 and T_H17 cytokine responses in the sensitization sites, and antigen-restimulated draining lymph node cells. In the papain-sensitized but not vehicle-treated mice, subsequent single challenge on the ear skin with papain, but not with protease inhibitor-treated papain, up-regulated the gene expression of T_H2 and T_H17/T_H22 cytokines along with cytokines promoting these T_H cytokine responses (TSLP, IL-33, IL-17C, and IL-23p19). Up-regulation of IL-17A gene expression and cells expressing RORγt occurred in the ear skin of the presensitized mice even before the challenge. In a reconstructed epidermal model with a three-dimensional culture of human keratinocytes, papain but not protease inhibitor-treated papain exhibited increasing transdermal permeability and stimulating the gene expression of TSLP, IL-17C, and IL-23p19. This study demonstrated that allergen protease activity contributed to the onset of cutaneous T_H2 and T_H17/T_H22 recall responses on allergen re-encounter at sites distant from the original epicutaneous sensitization exposures. This finding suggested the contribution of protease-dependent barrier disruption and induction of keratinocyte-derived cytokines to the recall responses.</p>","PeriodicalId":16073,"journal":{"name":"Journal of Immunotoxicology","volume":" ","pages":"118-126"},"PeriodicalIF":3.3,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39388912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Galangin ameliorates experimental autoimmune encephalomyelitis in mice via modulation of cellular immunity.","authors":"Kok-Tong Tan,&nbsp;Shiming Li,&nbsp;Lauren Panny,&nbsp;Chi-Chien Lin,&nbsp;Shih-Chao Lin","doi":"10.1080/1547691X.2021.1890863","DOIUrl":"https://doi.org/10.1080/1547691X.2021.1890863","url":null,"abstract":"<p><p>Multiple sclerosis (MS) causes neurologic disabilities that effect musculature, sensory systems, and vision. This is largely due to demyelination of nerve fibers caused by chronic inflammation. Corticosteroid treatments ameliorate symptoms of MS, but do not successfully cure the disease itself. In the current study, the application of galangin, a phytochemical flavonoid extracted from the ginger family of <i>Alpinis officinarum</i>, on experimental autoimmune encephalomyelitis (EAE; mouse model for MS) was explored. This study investigated prophylactic and therapeutic activity of the drug and mechanisms by which it acts. The results revealed that galangin at 40 and 80 mg/kg could lower the incidence rate of MS, and alleviate clinical/pathological manifestations. Mice administered galangin presented with less limb paralysis, lower levels of inflammatory cell infiltrates, and decreased demyelination compared to vehicle controls. Levels of CD4⁺IFNγ⁺ (T_H1) and CD4⁺IL-17A⁺ (T_H17) cells in the spinal cords of EAE mice administered galangin were reduced and both cell types were not capable of expansion. More surprisingly, galangin inhibited antigen presentation and cytokine production by dendritic cells (DC). Formation of cytokines like IL-6, IL-12, and IL-23 were significantly decreased due to galangin in co-culture models of DC and T-cells. Taken together, the data lead one to conclude that galangin could potentially be used as a potent immunoregulatory agent to alleviate clinical symptoms and reduce the prevalence of MS.</p>","PeriodicalId":16073,"journal":{"name":"Journal of Immunotoxicology","volume":" ","pages":"50-60"},"PeriodicalIF":3.3,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/1547691X.2021.1890863","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25519671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dietary advanced glycation end-products elicit toxicological effects by disrupting gut microbiome and immune homeostasis.","authors":"Yingjia Chen,&nbsp;Tai L Guo","doi":"10.1080/1547691X.2021.1959677","DOIUrl":"https://doi.org/10.1080/1547691X.2021.1959677","url":null,"abstract":"<p><p>The aging immune system is characterized by a low-grade chronic systemic inflammatory state (\"inflammaging\") marked by elevated serum levels of inflammatory molecules such as interleukin (IL)-6 and C-reactive protein (CRP). These inflammatory markers were also reported to be strong predictors for the development/severity of Type 2 diabetes, obesity, and COVID-19. The levels of these markers have been positively associated with those of advanced glycation end-products (AGEs) generated via non-enzymatic glycation and oxidation of proteins and lipids during normal aging and metabolism. Based on the above observations, it is clinically important to elucidate how dietary AGEs modulate inflammation and might thus increase the risk for aging-exacerbated diseases. The present narrative review discusses the potential pro-inflammatory properties of dietary AGEs with a focus on the inflammatory mediators CRP, IL-6 and ferritin, and their relations to aging in general and Type 2 diabetes in particular. In addition, underlying mechanisms - including those related to gut microbiota and the receptors for AGEs, and the roles AGEs might play in affecting physiologies of the healthy elderly, obese individuals, and diabetics are discussed in regard to any greater susceptibility to COVID-19.</p>","PeriodicalId":16073,"journal":{"name":"Journal of Immunotoxicology","volume":"18 1","pages":"93-104"},"PeriodicalIF":3.3,"publicationDate":"2021-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9885815/pdf/nihms-1865814.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10636841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Organic dust-induced lung injury and repair: Bi-directional regulation by TNFα and IL-10.","authors":"T A Wyatt, M Nemecek, D Chandra, J M DeVasure, A J Nelson, D J Romberger, J A Poole","doi":"10.1080/1547691X.2020.1776428","DOIUrl":"10.1080/1547691X.2020.1776428","url":null,"abstract":"<p><p>Exposure to organic dust increases chronic airway inflammatory disorders. Effective treatment strategies are lacking. It has been reported that hog barn dust extracts (HDE) induce TNFα through protein kinase C (PKC) activation and that lung inflammation is enhanced in scavenger receptor A (SRA/CD204) knockout (KO) mice following HDE. Because interleukin (IL)-10 production can limit excessive inflammation, it was hypothesized here that HDE-induced IL-10 would require CD204 to effect inflammatory responses. C57BL/6 wild-type (WT), SRA KO, and IL-10 KO mice were intranasally challenged daily for 8 days with HDE and subsequently rested for 3 days with/without recombinant IL-10 (rIL-10) treatment. Primary peritoneal macrophages (PM) and murine alveolar macrophages (MH-S cells) were treated <i>in vitro</i> with HDE, SRA ligand (fucoidan), rIL-10, and/or PKC isoform inhibitors. HDE induced <i>in vivo</i> lung IL-10 in WT, but not SRA KO mice, and similar trends were demonstrated in isolated PM from same treated mice. Lung lymphocyte aggregates and neutrophils were elevated in <i>in vivo</i> HDE-treated SRA and IL-10 KO mice after a 3-d recovery, and treatment during recovery with rIL-10 abrogated these responses. <i>In vitro</i> rIL-10 treatment reduced HDE-stimulated TNFα release in MH-S and WT PM. In SRA KO macrophages, there was reduced IL-10 and PKC zeta (ζ) activity and increased TNFα following <i>in vitro</i> HDE stimulation. Similarly, blocking SRA (24 hr fucoidan pre-treatment) resulted in enhanced HDE-stimulated macrophage TNFα and decreased IL-10 and PKCζ activation. PKCζ inhibitors blocked HDE-stimulated IL-10, but not TNFα. Collectively, HDE stimulates IL-10 by an SRA- and PKCζ-dependent mechanism to regulate TNFα. Enhancing resolution of dust-mediated lung inflammation through targeting IL-10 and/or SRA may represent new approaches to therapeutic interventions.</p>","PeriodicalId":16073,"journal":{"name":"Journal of Immunotoxicology","volume":"17 1","pages":"153-162"},"PeriodicalIF":2.4,"publicationDate":"2020-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11238278/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10770903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>In vivo</i> assessment of respiratory burst inhibition by xenobiotic exposure using larval zebrafish.","authors":"Drake W Phelps,&nbsp;Ashley A Fletcher,&nbsp;Ivan Rodriguez-Nunez,&nbsp;Michele R Balik-Meisner,&nbsp;Debra A Tokarz,&nbsp;David M Reif,&nbsp;Dori R Germolec,&nbsp;Jeffrey A Yoder","doi":"10.1080/1547691X.2020.1748772","DOIUrl":"https://doi.org/10.1080/1547691X.2020.1748772","url":null,"abstract":"<p><p>Currently, assessment of the potential immunotoxicity of a given agent involves a tiered approach for hazard identification and mechanistic studies, including observational studies, evaluation of immune function, and measurement of susceptibility to infectious and neoplastic diseases. These studies generally use costly low-throughput mammalian models. Zebrafish, however, offer an excellent alternative due to their rapid development, ease of maintenance, and homology to mammalian immune system function and development. Larval zebrafish also are a convenient model to study the innate immune system with no interference from the adaptive immune system. In this study, a respiratory burst assay (RBA) was utilized to measure reactive oxygen species (ROS) production after developmental xenobiotic exposure. Embryos were exposed to non-teratogenic doses of chemicals and at 96 h post-fertilization, the ability to produce ROS was measured. Using the RBA, 12 compounds with varying immune-suppressive properties were screened. Seven compounds neither suppressed nor enhanced the respiratory burst; five reproducibly suppressed global ROS production, but with varying potencies: benzo[a]pyrene, 17β-estradiol, lead acetate, methoxychlor, and phenanthrene. These five compounds have all previously been reported as immunosuppressive in mammalian innate immunity assays. To evaluate whether the suppression of ROS by these compounds was a result of decreased immune cell numbers, flow cytometry with transgenic zebrafish larvae was used to count the numbers of neutrophils and macrophages after chemical exposure. With this assay, benzo[a]pyrene was found to be the only chemical that induced a change in the number of immune cells by increasing macrophage but not neutrophil numbers. Taken together, this work demonstrates the utility of zebrafish larvae as a vertebrate model for identifying compounds that impact innate immune function at non-teratogenic levels and validates measuring ROS production and phagocyte numbers as metrics for monitoring how xenobiotic exposure alters the innate immune system.</p>","PeriodicalId":16073,"journal":{"name":"Journal of Immunotoxicology","volume":" ","pages":"94-104"},"PeriodicalIF":3.3,"publicationDate":"2020-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/1547691X.2020.1748772","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37933790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prenatal arsenic exposure interferes in postnatal immunocompetence despite an absence of ongoing arsenic exposure.","authors":"Mainak Chakraborty,&nbsp;Moumita Bhaumik","doi":"10.1080/1547691X.2020.1767238","DOIUrl":"https://doi.org/10.1080/1547691X.2020.1767238","url":null,"abstract":"<p><p>Arsenic (As) readily crosses the placenta and exposure of the fetus may cause adverse consequences later in life, including immunomodulation. In the current study, the question was asked how the immune repertoire might respond in postnatal life when there is no further As exposure. Here, pregnant mice (Balb/c [H-2^d]) were exposed to arsenic trioxide (As₂O₃) through their drinking water from time of conception until parturition. Their offspring, 4-week-old mice who had not been exposed again to As, were used for functional analyses of innate, humoral and cellular immunity. Compared to cells from non-As-exposed dam offspring, isolated peritoneal macro-phages (Mϕ) displayed no differences in T-cell stimulating ability. Levels of circulating IgG_2a but not IgG₁ were decreased in As-exposed dam offspring as compared to control offspring counterparts. Mixed-leukocyte reactions (MLR) indicated that CD4⁺ T-cells from the prenatal As-exposed mice were significantly less responsive to allogenic stimulation as evidenced by decreases in interferon (IFN)-γ and IL-2 production and in expression of CD44 and CD69 (but not CD25) activation markers. Interestingly, the Mϕ from the prenatal As-exposed mice were capable of stimulating normal allogenic T-cells, indicating that T-cells from these mice were refractory to allogenic signals. There was also a significant decrease in absolute numbers of splenic CD4⁺ and CD8⁺ T-cells due to prenatal As exposure (as compared to control). Lastly, the impaired immune function of the prenatal As-exposed mice was correlated with a very strong susceptibility to <i>Escherichia coli</i> infection. Taken together, the data from this study clearly show that <i>in utero</i> As exposure may continue to perpetuate a dampening effect on the immune repertoire of offspring, even into the early stages of postnatal life.</p>","PeriodicalId":16073,"journal":{"name":"Journal of Immunotoxicology","volume":" ","pages":"135-143"},"PeriodicalIF":3.3,"publicationDate":"2020-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/1547691X.2020.1767238","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38044514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential classification of chemical immunologic response based on gene expression profiles.","authors":"Stacey E Anderson, Rachel Baur, Michael Kashon, Ewa Lukomska, Lisa Weatherly, Hillary L Shane","doi":"10.1080/1547691X.2020.1758855","DOIUrl":"10.1080/1547691X.2020.1758855","url":null,"abstract":"<p><p>Occupational immune diseases are a serious public health burden and are often a result of exposure to low molecular weight (LMW) chemicals. The complete immunological mechanisms driving these responses are not fully understood which has made the classification of chemical allergens difficult. Antimicrobials are a large group of immunologically-diverse LMW agents. In these studies, mice were dermally exposed to representative antimicrobial chemicals (sensitizers: didecyldimethylammonium chloride (DDAC), <i>ortho</i>-phthalaldehyde (OPA), irritants: benzal-konium chloride (BAC), and adjuvant: triclosan (TCS)) and the mRNA expression of cytokines and cellular mediators was evaluated using real-time qPCR in various tissues over a 7-days period. All antimicrobials caused increases in the mRNA expression of the danger signals <i>Tslp</i> (skin), and <i>S100a8</i> (skin, blood, lung). Expression of the T_H2 cytokine <i>Il4</i> peaked at different timepoints for the chemicals based on exposure duration. Unique expression profiles were identified for OPA (<i>Il10</i> in lymph node, <i>Il4</i> and <i>Il13</i> in lung) and TCS (<i>Tlr4</i> in skin). Additionally, all chemicals except OPA induced decreased expression of the cellular adhesion molecule <i>Ecad</i>. Overall, the results from these studies suggest that unique gene expression profiles are implicated following dermal exposure to various antimicrobial agents, warranting the need for additional studies. In order to advance the development of preventative and therapeutic strategies to combat immunological disease, underlying mechanisms of antimicrobial-induced immunomodulation must be fully understood. This understanding will aid in the development of more effective methods to screen for chemical toxicity, and may potentially lead to more effective treatment strategies for those suffering from immune diseases.</p>","PeriodicalId":16073,"journal":{"name":"Journal of Immunotoxicology","volume":" ","pages":"122-134"},"PeriodicalIF":2.4,"publicationDate":"2020-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673648/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37972674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of aryl hydrocarbon receptor (AhR) in mesenchymal stem cells modulates macrophage polarization in asthma.","authors":"Zhuang Cui,&nbsp;Yuan Feng,&nbsp;Danqing Li,&nbsp;Taoping Li,&nbsp;Peisong Gao,&nbsp;Ting Xu","doi":"10.1080/1547691X.2019.1706671","DOIUrl":"https://doi.org/10.1080/1547691X.2019.1706671","url":null,"abstract":"<p><p>Macrophage polarization has been demonstrated to exert a vital role on asthma pathogenesis. Mesenchymal stem cells (MSC) have the capacity to modulate macrophage differentiation from a pro-inflammatory M1 phenotype toward an anti-inflammatory M2 phenotype. However, the impact of MSC-macrophage interactions on asthma development and underlying mechanisms responsible for this interaction remain largely unknown. The aim of this study was to investigate the role of AhR expressed on MSC in macrophage polarization in a cockroach extract (CRE)-induced asthma mouse model. The studies here revealed that MSC polarized macrophages from a pro-inflammatory M1 phenotype toward an anti-inflammatory M2 phenotype in this model. The mRNA levels of interleukin (IL)-6, IL-1β, and NOS2 as M1 markers were significantly decreased while those of select M2 markers such as Arg-1, FIZZ1, and YM-1 were significantly enhanced. It was also observed that aryl hydrocarbon receptor (AhR) signaling was significantly increased during asthma pathogenesis as demonstrated by enhanced mRNA expression of AhR, CYP1a1, and CYP1b1. It was also seen that the elevated AhR signaling was able to attenuate the onset of asthma. Use of an AhR antagonist (CH223191) resulted in significant inhibition of the AhR signaling and increases in M2 marker expression, but led to elevation of expression of M1 markers in the CRE-induced asthma model. Taken together, the current study showed that MSC can modulate macrophage polarization, in part, via activation of AhR signaling during CRE-induced asthma.</p>","PeriodicalId":16073,"journal":{"name":"Journal of Immunotoxicology","volume":" ","pages":"21-30"},"PeriodicalIF":3.3,"publicationDate":"2020-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/1547691X.2019.1706671","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37530027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Colostrum fails to prevent bovine/camelid neonatal neutrophil damage from AFB₁.","authors":"Sajad Najafi,&nbsp;Gholamreza Mohammadi,&nbsp;Mehrdad Mohri,&nbsp;Saman Hosseinkhani,&nbsp;Jalil Mehrzad","doi":"10.1080/1547691X.2020.1725693","DOIUrl":"https://doi.org/10.1080/1547691X.2020.1725693","url":null,"abstract":"<p><p>Exposure to environmental toxicants that affect the immune system and overall health of many mammals is mostly unavoidable. One of the more common substances is the mycotoxins, especially carcinogenic aflatoxin (AF)B₁ which also causes immune suppression/dysregulation in exposed hosts. The present study analyzed the effects of naturally occurring levels of AFB₁ on apoptosis of healthy bovine and camelid neonatal neutrophils (PMN) that were isolated both before and after host consumption of colostrum. Cells from bovine and camel neonates (<i>n</i> = 12 sets of PMN/mammal/timepoint) were exposed for 24 h to a low level of AFB₁ (i.e. 10 ng AFB₁/ml) and then intracellular ATP content and caspase-3, -7, and -9 activities (determined by bioluminescence) were assessed. The results indicated a significant lessening of intracellular ATP content and equivalents of luminescence intensity in AFB₁-treated PMN in all studied samples, i.e. isolated pre-and post-colostrum consumption. In contrast, caspase-3, -7, and -9 activities in both pre- and post-colostrum consumption bovine and camelid PMN were noticeably increased (∼>2-fold). The damaging effects of AFB₁ were more pronounced in bovine neonate PMN than in camelid ones. These results showed that camelid or bovine neonatal PMN collected pre- and post-colostrum are sensitive (moreso after consumption) to naturally occurring levels of AFB₁. While merits of colostrum are well known, its failure to mitigate toxic effects of AFB₁ in what would translate into a critical period in the development of immune competence (i.e. during the first few days of life in bovine and camelid calves) is surprising. The observed <i>in vitro</i> toxicities can help clarify underlying mechanisms of immune disorders caused by AFs in animals/humans.</p>","PeriodicalId":16073,"journal":{"name":"Journal of Immunotoxicology","volume":" ","pages":"43-50"},"PeriodicalIF":3.3,"publicationDate":"2020-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/1547691X.2020.1725693","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37699843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MRGPRX2 activation as a rapid, high-throughput mechanistic-based approach for detecting peptide-mediated human mast cell degranulation liabilities.","authors":"Marc A Lafleur,&nbsp;Jonathan Werner,&nbsp;Madeline Fort,&nbsp;Edward K Lobenhofer,&nbsp;Mercedesz Balazs,&nbsp;Ana Goyos","doi":"10.1080/1547691X.2020.1757793","DOIUrl":"https://doi.org/10.1080/1547691X.2020.1757793","url":null,"abstract":"<p><p>Mast cells play key roles in allergy, anaphylaxis/anaphylactoid reactions, and defense against pathogens/toxins. These cells contain cytoplasmic granules with a wide spectrum of pleotropic mediators that are released upon activation. While mast cell degranulation (MCD) occurs upon clustering of the IgE receptor bound to IgE and antigen, MCD is also triggered through non-IgE-mediated mechanisms, one of which is via Mas-related G protein-coupled receptor X2 (MRGPRX2). MRGPRX2 can be activated by many basic biogenic amines and peptides. Consequently, MRGPRX2-mediated MCD is an important potential safety liability for peptide therapeutics. To facilitate peptide screening for this liability in early preclinical drug development, a rapid, high-throughput engineered CHO-K1 cell-based MRGPRX2 activation assay was evaluated and compared to histamine release in CD34⁺ stem cell-derived mature human mast cells as a reference assay, using 30 positive control and 29 negative control peptides for MCD. Both G protein-dependent (Ca²⁺ endpoint) and -independent (β-arrestin endpoint) pathways were assessed in the MRGPRX2 activation assay. The MRGPRX2 activation assay had a sensitivity of 100% for both Ca²⁺ and β-arrestin endpoints and a specificity of 93% (β-arrestin endpoint) and 83% (Ca²⁺ endpoint) compared to histamine release in CD34⁺ stem cell-derived mature human mast cells. These findings suggest that assessing MRGPRX2 activation in an engineered cell model can provide value as a rapid, high-throughput, economical mechanism-based screening tool for early MCD hazard identification during preclinical safety evaluation of peptide-based therapeutics.</p>","PeriodicalId":16073,"journal":{"name":"Journal of Immunotoxicology","volume":" ","pages":"110-121"},"PeriodicalIF":3.3,"publicationDate":"2020-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/1547691X.2020.1757793","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38032916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}